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PubMed2002

Cannabinoids and brain injury: therapeutic implications.

Mounting in vitro and in vivo data suggest that the endocannabinoids anandamide and 2-arachidonoyl glycerol, as well as some plant and synthetic cannabinoids, have neuroprotective effects following brain injury. Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission and reduce the production of tumour necrosis factor-alpha and reactive oxygen intermediates, which are factors in causing neuronal damage. The formation of the endocannabinoids anandamide and 2-arachidonoyl glycerol is strongly enhanced after brain injury, and there is evidence that these compounds reduce the secondary damage incurred. Some plant and synthetic cannabinoids, which do not bind to the cannabinoid receptors, have also been shown to be neuroprotective, possibly through their direct effect on the excitatory glutamate system and/or as antioxidants.

Animals↗
PubMed2001

Selective oxygenation of the endocannabinoid 2-arachidonylglycerol by leukocyte-type 12-lipoxygenase.

The endogenous cannabinoid system appears to serve vascular, neurological, immunological, and reproductive functions. The identification of 2-arachidonylglycerol (2-AG) as an endogenous ligand for the central (CB1) and peripheral (CB2) cannabinoid receptors has prompted interest in enzymes capable of modifying or inactivating this endocannabinoid. Porcine leukocyte 12-liopoxygenase (12-LOX) oxygenated 2-AG to the 2-glyceryl ester of 12(S)-hydroperoxyeicosa-5,8,10,14-tetraenoic acid (12-HPETE-G). The k(cat)/K(M) for oxygenation of 2-AG was 40% of the value for arachidonic acid. In contrast to the results with leukocyte 12-LOX, 2-AG oxygenation was not detected with platelet-type 12-LOX. Among a series of structurally related arachidonyl esters, 2-AG served as the preferential substrate for leukocyte 12-LOX. 12(S)-Hydroxyeicosa-5,8,10,14-tetraenoic acid glyceryl ester (12-HETE-G) was produced following addition of 2-AG to COS-7 cells transiently transfected with leukocyte 12-LOX. These results demonstrate that leukocyte-type 12-LOX efficiently oxidizes 2-AG in vitro and in intact cells, suggesting a role for this oxygenase in the endogenous cannabinoid system.

Animals↗
PubMed2003

Amino acid determinants in cyclooxygenase-2 oxygenation of the endocannabinoid anandamide.

The endocannabinoid arachidonylethanolamide (AEA, anandamide) is an endogenous ligand for the cannabinoid receptors and has been shown to be oxygenated by cyclooxygenase-2 (COX-2). We examined the structural requirements for COX-mediated, AEA oxygenation using a number of substrate analogues and site-directed mutants of COX-2. Fourteen AEA analogues were synthesized and tested as COX substrates. These studies identified the hydroxyl moiety of AEA as a critical determinant in the ability of COX enzymes to effect robust endocannabinoid oxygenation. In addition, these studies suggest that subtle structural modifications of AEA analogues near the ethanolamide moiety can result in pronounced changes in their ability to serve as COX-2 substrates. Site-directed mutagenesis studies have permitted the development of a model of AEA binding within the COX-2 active site. As with arachidonic acid, the omega-terminus of AEA binds in a hydrophobic alcove near the top of the COX-2 active site. The polar ethanolamide moiety of AEA, like the carboxylate of arachidonate, interacts with Arg-120 at the bottom of the COX-2 active site. Mutation of Tyr-385 prevents AEA oxygenation, suggesting that, as in the case of other COX substrates, AEA metabolism is initiated by Tyr-385-mediated hydrogen abstraction. Thus, AEA binds within the COX-2 active site in a conformation roughly similar to that of arachidonic acid. However, important differences have been identified that account for the isoform selectivity of AEA oxygenation. Importantly, the COX-2 side pocket and Arg-513 in particular are critical determinants of the ability of COX-2 to efficiently generate prostaglandin H(2) ethanolamide. The reduced efficiency of COX-1-mediated, AEA oxygenation can thus be explained by the absence of an arginine residue at position 513 in this isoform. Mutational analysis of Leu-531, an amino acid located directly across from the COX-2 side pocket, suggests that AEA is shifted away from this hydrophobic residue and toward Arg-513 relative to arachidonic acid. Coupled with earlier observations with the endocannabinoid 2-arachidonylglycerol, these results indicate that one possible function of the highly conserved COX-2 active site side pocket is to promote endocannabinoid oxygenation.

Acetylation↗
PubMed2000

Comparison of novel cannabinoid partial agonists and SR141716A in the guinea-pig small intestine.

The controversial nature of the CB(1) receptor antagonist, SR141716A, in the guinea-pig small intestine was investigated by comparing it with four analogues of Delta(8)-tetrahydrocannabinol (Delta(8)-THC): O-1184, O-1238, O-584 and O-1315. These compounds (10 - 1000 nM) inhibited the electrically-evoked contractions with a rank order of potency of O-1238>O-1184>O-584>O-1315. Log concentration-response curves for O-1238, O-1184 and O-1315 were significantly shifted to the right by SR141716A and the maxima were significantly less than that of the CB(1) agonist, WIN55212-2, an indication of partial agonism. Partial saturation of the triple bond in O-1184 to a cis double bond (O-1238) increased its potency as an agonist (pEC(50) from 6.42 to 7.63) and as an antagonist of WIN55212-2, (pK(B), from 8.36 to 9.49). Substitution of the terminal azide group by an ethyl group (O-584) or removal of the phenolic hydroxyl group (O-1315) had no significant effect on the agonist or antagonist potency. None of these analogues increased the twitch response in a manner resembling that of SR141716A. O-1184 (10 and 100 nM) shifted the log concentration-response curve of WIN55212-2 for inhibition of the twitch responses to the right with pK(B) values of 8.29 and 8.38, respectively. We conclude that these Delta(8)-THC analogues behave as partial agonists rather than silent antagonists at CB(1) binding sites in this tissue. There was no evidence of antagonism of endocannabinoids thus supporting the hypothesis that, in this tissue, SR141716A is an inverse agonist of constitutively active CB(1) receptors.

Animals↗
PubMed2002

Role of the endocannabinoid system in MDMA intracerebral self-administration in rats.

I.c.v. self-administration of MDMA (0.01-2 micro g per infusion), alone and in combination with CP 55,940 (0.4 micro g infusion(-1)), was studied on an operant responding procedure. On the basis of individual preference for one of two levers, developed during training, rats were allowed to self-administer vehicle from the preferred lever and MDMA from the other. Pressings on the MDMA associated-lever, except for the maximal unit dose, progressively increased. The combination of CP 55,940 with MDMA (1 micro g infusion(-1)) reduced the number of drug-associated lever pressings compared to the single drugs. Pre-treatment with SR 141716A (0.5 mg kg(-1) i.p.), 15 min before each daily session, significantly increased MDMA self-administration. These findings suggest that MDMA self-administration is under endogenous tonic control by the endocannabinoid system.

Animals↗
PubMed2005

Cannabinoid agonists but not inhibitors of endogenous cannabinoid transport or metabolism enhance the reinforcing efficacy of heroin in rats.

Accumulating evidence suggests that the endogenous cannabinoid system is involved in the reinforcing effects of heroin. In rats intravenously self-administering heroin, we investigated effects of cannabinoid CB1 receptor agonists and compounds that block transport or metabolism of the endogenous cannabinoid anandamide. The natural cannnabinoid CB1 receptor agonist delta-9-tetrahydrocannabinol (THC, 0.3-3 mg/kg i.p.) did not alter self-administration of heroin under a fixed-ratio one (FR1) schedule, except at a high 3 mg/kg dose which decreased heroin self-administration. Under a progressive-ratio schedule, however, THC dose-dependently increased the number of 50 mug/kg heroin injections self-administered per session and the maximal ratio completed (break-point), with peak increases at 1 mg/kg THC. In addition, 1 mg/kg THC increased break-points and injections self-administered over a wide range of heroin injection doses (25-100 microg/kg), indicating an increase in heroin's reinforcing efficacy and not its potency. The synthetic cannabinoid CB1 receptor agonist WIN55,212-2 (0.3-3 mg/kg i.p.) had effects similar to THC under the progressive-ratio schedule. In contrast, AM-404 (1-10 mg/kg i.p.), an inhibitor of transport of anandamide, and URB-597 (0.01-0.3 mg/kg i.p.), an inhibitor of the enzyme fatty acid amide hydrolase (FAAH) that degrades anandamide, or their combination, did not increase reinforcing efficacy of heroin at any dose tested. Thus, activation of cannabinoid CB1 receptors facilitates the reinforcing efficacy of heroin and this appears to be mediated by interactions between cannabinoid CB1 receptors and mu-opioid receptors and their signaling pathways, rather than by an opioid-induced release of endogenous cannabinoids.

Animals↗
PubMed2002

Binding, degradation and apoptotic activity of stearoylethanolamide in rat C6 glioma cells.

Stearoylethanolamide (SEA) is present in human, rat and mouse brain in amounts comparable with those of the endocannabinoid anandamide (arachidonoylethanolamide; AEA). Yet, the biological activity of SEA has never been investigated. We synthesized unlabelled and radiolabelled SEA to investigate its binding, degradation and biological activity in rat C6 glioma cells. We report that SEA binds to a specific site distinct from known cannabinoid or vanilloid receptors, and that AEA and capsazepine partly (approx. 50%) antagonized this binding. Treatment of C6 cells with SEA inhibits cellular nitric oxide synthase and does not affect adenylate cyclase, whereas treatment with cannabinoid type 1 agonist 2-arachidonoylglycerol activates the former enzyme and inhibits the latter. C6 cells also have a specific SEA membrane transporter, which is inhibited by NO, and a fatty acid amide hydrolase capable of cleaving SEA. In these cells, SEA shows pro-apoptotic activity, due to elevation of intracellular calcium, activation of the arachidonate cascade and mitochondrial uncoupling. NO further enhances SEA-induced apoptosis. Moreover, the cannabinoid type 1 receptor-mediated decrease in cAMP induced by AEA in C6 cells is potentiated by SEA, suggesting that this compound also has an 'entourage' effect. Taken together, this study shows that SEA is an endocannabinoid-like compound which binds to and is transported by new components of the endocannabinoid system. It seems noteworthy that degradation and pro-apoptotic activity of SEA are regulated by NO in a way opposite to that reported for AEA.

Animals↗
PubMed1998

The novel endogenous cannabinoid 2-arachidonoylglycerol is inactivated by neuronal- and basophil-like cells: connections with anandamide.

The novel endogenous cannabinoid 2-arachidonoylglycerol (2-AG) was rapidly inactivated by intact rat basophilic leukaemia (RBL-2H3) and mouse neuroblastoma (N18TG2) cells through diffusion/hydrolysis/reacylation processes. The hydrolysis of 2-AG was inhibited by typical esterase inhibitors and by more specific blockers of 'fatty acid amide hydrolase' (FAAH), the enzyme catalysing the hydrolysis of the other 'endocannabinoid', anandamide (AEA). No evidence for a facilitated-diffusion process was found. A 2-AG-hydrolysing activity was detected in homogenates from both cell lines, with the highest levels in membrane fractions. It exhibited an optimal pH at 10, and recognized both 2- and 1(3)- isomers of monoarachidonoylglycerol with similar efficiencies. The apparent Km and Vmax values for -3H-2-AG hydrolysis were 91 microM and 29 microM and 2.4 and 1.8 nmol.min-1.mg of protein-1 respectively in N18TG2 and RBL-2H3 cells. [3H]2-AG hydrolysis was inhibited by Cu2+, Zn2+ and p-hydroxymercuribenzoate, and by 2- or 1(3)-monolinoleoyl- and -linolenoyl-glycerols, but not by the oleoyl, palmitoyl and myristoyl congeners. Purified fractions from solubilized membrane proteins catalysed, at pH 9.5, the hydrolysis of 2-AG as well as AEA. Accordingly, AEA as well as FAAH inhibitors, including arachidonoyltrifluoromethyl ketone (ATFMK), blocked [3H]2-AG hydrolysis by N18TG2 and RBL-2H3 membranes, whereas 2-AG inhibited [14C]AEA hydrolysis. FAAH blockade by ATFMK preserved from inactivation the 2-AG synthesized de novo by intact N18TG2 cells stimulated with ionomycin. These data suggest that FAAH may be one of the enzymes deputed to the physiological inactivation of 2-AG, and create intriguing possibilities for the cross-regulation of 2-AG and AEA levels.

Amidohydrolases↗
PubMed2003

Uptake and metabolism of [3H]anandamide by rabbit platelets. Lack of transporter?

Anandamide is an endogenous ligand for cannabinoid receptor and its protein-mediated transport across cellular membranes has been demonstrated in cells derived from brain as well as in cells of the immune system. This lipid is inactivated via intracellular degradation by a fatty acid amidohydrolase (FAAH). In the present study, we report that rabbit platelets, in contrast to human platelets, do not possess a carrier-mediated mechanism for the transport of [3H]anandamide into the cell, i.e. cellular uptake was not temperature dependent and its accumulation was not saturable. This endocannabinoid appears to enter the cell by simple diffusion. Once taken up by rabbit platelets, [3H]anandamide was rapidly metabolized into compounds which were secreted into the medium. Small amounts of free arachidonic acid as well as phospholipids were amongst the metabolic products. FAAH inhibitors did not decrease anandamide uptake, whereas these compounds inhibited anandamide metabolism. In conclusion, anandamide is rapidly taken up by rabbit platelets and metabolized mainly into water-soluble metabolites. Interestingly, the present study also suggests the absence of a transporter for anandamide in these cells.

Amidohydrolases↗
PubMed2001

Anticonvulsant activity of N-palmitoylethanolamide, a putative endocannabinoid, in mice.

PURPOSE: The purpose of this study was to evaluate in mice the anticonvulsant potential of N-palmitoylethanolamide, a putative endocannabinoid that accumulates in the body during inflammatory processes. METHODS: N-palmitoylethanolamide was injected intraperitoneally (i.p.) in mice and evaluated for anticonvulsant activity [in maximal electroshock seizure (MES) and chemical-induced convulsions] and for neurologic impairment (rotorod). It was compared with anandamide and with different palmitic acid analogues as well as with reference anticonvulsants (AEDs) injected under the same conditions. RESULTS: The MES test showed, after i.p. administration to mice, that N-palmitoy]ethanolamide had an median effective dose (ED50) value comparable to that of phenytoin (PHT; 8.9 and 9.2 mg/kg, respectively). In the subcutaneous pentylenetetrazol test and in the 3-mercaptropropionic acid test, it was effective only against tonic convulsions. N-palmitoylethanolamide was devoid of neurologic impairment < or = 250 mg/kg, yielding a high protective index. CONCLUSIONS: N-palmitoylethanolamide, an endogenous compound with antiinflammatory and analgesic activities, is a potent AED in mice. Its precise mechanism of action remains to be elucidated.

Amides↗
PubMed2000

Is platelet release of 2-arachidonoyl-glycerol a mediator of cognitive deficits? An endocannabinoid theory of schizophrenia and arousal.

The discovery of blood platelet's ability to release 2-arachidonoyl-glycerol (2-AG), a highly lipophilic cannabinoid molecule may usher in a radical change in our understanding of how the vascular system interacts with the brain. This paper primarily extends Kayai's second messenger imbalance theory of schizophrenia, suggesting that 2-AG is the unidentified second messenger system that Kayai theorized was unbalanced in schizophrenia; furthermore, that a chronic over-release of 2-AG by platelets may be a causal factor in the cognitive deficits associated with negative symptom schizophrenia. Finally, platelet release of 2-AG may also be the causal agent in the cognitive deficits associated with states of high arousal, shock and in other conditions that feature heightened platelet activation. As such, heightened platelet activation may be a profoundly important vector for changing endogenous cannabinoid levels in the brain.

Antipsychotic Agents↗
PubMedDate not supplied

Cellular transport of anandamide, 2-arachidonoylglycerol and palmitoylethanolamide--targets for drug development?

The endogenous cannabinoid anandamide (AEA) is transported into cells by a temperature-sensitive process of facilitated diffusion. This uptake process has been characterised both biochemically and pharmacologically, and shown to be regulated at least in part by the intracellular metabolism of the accumulated AEA by fatty acid amide hydrolase. In this review, the properties of this transport process are briefly reviewed together with the corresponding transport mechanisms for the related endogenous compounds 2-arachidonoylglycerol and palmitoylethanolamide. In addition, the possibility that these transport mechanisms can be targets for therapeutic strategies aimed at prolonging the effects of the endocannabinoids is discussed.

Amides↗
PubMedDate not supplied

Oxidative metabolism of endocannabinoids.

There is increasing evidence that endocannabinoids play roles in a number of physiological and pathological processes ranging from the regulation of food intake to the inhibition of cancer cell proliferation. Consequently, multiple investigations into endocannabinoid metabolic disposition have been initiated. Such studies have begun to shed light on the mechanisms that regulate the endogenous cannabinoid system. In addition, they have identified a number of novel, endocannabinoid-derived lipids. In the future, these studies may form the foundation of efforts designed to subtly manipulate endocannabinoid tone in vivo to achieve therapeutic benefits without the profound side-effects observed with synthetic cannabinoid treatment. In addition to the well-studied hydrolytic mode of endocannabinoid metabolism, accumulating data suggest that these lipids are also susceptible to oxidative metabolism by a number of fatty acid oxygenases. These include the cyclooxygenases, lipoxygenases, and cytochrome P450s known to be involved in eicosanoid production from arachidonic acid. The available evidence concerning endocannabinoid oxidation is reviewed and the potential biological significance of this mode of metabolism is considered.

Animals↗
PubMed2002

Brain monoglyceride lipase participating in endocannabinoid inactivation.

The endogenous cannabinoids (endocannabinoids) are lipid molecules that may mediate retrograde signaling at central synapses and other forms of short-range neuronal communication. The monoglyceride 2-arachidonoylglycerol (2-AG) meets several criteria of an endocannabinoid substance: (i) it activates cannabinoid receptors; (ii) it is produced by neurons in an activity-dependent manner; and (iii) it is rapidly eliminated. 2-AG inactivation is only partially understood, but it may occur by transport into cells and enzymatic hydrolysis. Here we tested the hypothesis that monoglyceride lipase (MGL), a serine hydrolase that converts monoglycerides to fatty acid and glycerol, participates in 2-AG inactivation. We cloned MGL by homology from a rat brain cDNA library. Its cDNA sequence encoded for a 303-aa protein with a calculated molecular weight of 33,367 daltons. Northern blot and in situ hybridization analyses revealed that MGL mRNA is heterogeneously expressed in the rat brain, with highest levels in regions where CB(1) cannabinoid receptors are also present (hippocampus, cortex, anterior thalamus, and cerebellum). Immunohistochemical studies in the hippocampus showed that MGL distribution has striking laminar specificity, suggesting a presynaptic localization of the enzyme. Adenovirus-mediated transfer of MGL cDNA into rat cortical neurons increased MGL expression and attenuated N-methyl-D-aspartate/carbachol-induced 2-AG accumulation in these cells. No such effect was observed on the accumulation of anandamide, another endocannabinoid lipid. The results suggest that hydrolysis by means of MGL is a primary mechanism for 2-AG inactivation in intact neurons.

Amino Acid Sequence↗
PubMed2001

Amino acid determinants in cyclooxygenase-2 oxygenation of the endocannabinoid 2-arachidonylglycerol.

The endocannabinoid, 2-arachidonylglycerol (2-AG), is an endogenous ligand for the central (CB1) and peripheral (CB2) cannabinoid receptors and has been shown to be efficiently and selectively oxygenated by cyclooxygenase (COX)-2. We have investigated 2-AG/COX-2 interactions through site-directed mutagenesis. An evaluation of more than 20 site-directed mutants of murine COX-2 has allowed for the development of a model of 2-AG binding within the COX-2 active site. Most strikingly, these studies have identified Arg-513 as a critical determinant in the ability of COX-2 to efficiently generate prostaglandin H(2) glycerol ester, explaining, in part, the observed isoform selectivity for this substrate. Mutational analysis of Leu-531, an amino acid located directly across from Arg-513 in the COX-2 active site, suggests that 2-AG is shifted in the active site away from this hydrophobic residue and toward Arg-513 relative to arachidonic acid. Despite this difference, aspirin-treated COX-2 oxygenates 2-AG to afford 15-hydroxyeicosatetraenoic acid glycerol ester in a reaction analogous to the C-15 oxygenation of arachidonic acid observed with acetylated COX-2. Finally, the differences in substrate binding do not alter the stereospecificity of the cyclooxygenase reaction; 2-AG-derived and arachidonic acid-derived products share identical stereochemistry.

Amino Acid Sequence↗
PubMed2002

Metabolism of the endocannabinoids, 2-arachidonylglycerol and anandamide, into prostaglandin, thromboxane, and prostacyclin glycerol esters and ethanolamides.

Cyclooxygenase-2 (COX-2) action on the endocannabinoids, 2-arachidonylglycerol (2-AG) and anandamide (AEA), generates prostaglandin glycerol esters (PG-G) and ethanolamides (PG-EA), respectively. The diversity of PG-Gs and PG-EAs that can be formed enzymatically following COX-2 oxygenation of endocannabinoids was examined in cellular and subcellular systems. In cellular systems, glycerol esters and ethanolamides of PGE(2), PGD(2), and PGF(2alpha) were major products of the endocannabinoid-derived COX-2 products, PGH(2)-G and PGH(2)-EA. The sequential action of purified COX-2 and thromboxane synthase on AEA and 2-AG provided thromboxane A(2) ethanolamide and glycerol ester, respectively. Similarly, bovine prostacyclin synthase catalyzed the isomerization of the intermediate endoperoxides, PGH(2)-G and PGH(2)-EA, to the corresponding prostacyclin derivatives. Quantification of the efficiency of prostaglandin and thromboxane synthase-directed endoperoxide isomerization demonstrated that PGE, PGD, and PGI synthases catalyze the isomerization of PGH(2)-G at rates approaching those observed with PGH(2). In contrast, thromboxane synthase was far more efficient at catalyzing PGH(2) isomerization than at catalyzing the isomerization of PGH(2)-G. These results define the in vitro diversity of endocannabinoid-derived prostanoids and will permit focused investigations into their production and potential biological actions in vivo.

Animals↗